Researchers at The University of Texas M. D. Anderson Cancer Center have identified a possible biomarker for determining the risk of lung cancer as well as tracking the effectiveness of chemoprevention strategies.

The possible biomarker is Ki-67, a protein found in all phases of cell proliferation, a biological process that is dysregulated during tumor development.

M. D. Anderson researchers measured cell-growth response in bronchial specimens taken from more than 325 smokers and non-smokers. They found that smoking induces a dose-related cell-growth response in the lung linings of active smokers. In former smokers, there is a decreased, yet still detectable, cell-growth response. Because abnormal cell proliferation is often an early hallmark for tumor development, Ki-67 could be a highly useful biomarker to help identify individuals at the highest risk for lung cancer and better assess response to chemoprevention measures, report researchers.

The study is reported in the July 18 issue of the Journal of the National Cancer Institute (JNCI) and is accompanied by an editorial by Dr. Eva Szabo of the National Institutes of Health.

An emerging field at M. D. Anderson, chemoprevention is the use of drugs or chemicals to intercept and interrupt the biological processes that may lead to cancer. M. D. Anderson currently has a lung cancer chemoprevention trial under way in which former smokers are given either 13-cis retinoic acid, a synthetic vitamin A analogue, plus vitamin E or 9-cis retinoic acid, another synthetic analogue, or a placebo. The goal of the study now in progress at M. D. Anderson is to determine if chemoprevention measures can reverse the biological processes caused by smoking, that often can lead to lung cancer.

"There is still much long-term research to be done on the use of Ki-67 as a possible biomarker for identifying individuals at the highest risk for lung cancer and how well they respond to chemoprevention," said Dr. J. Jack Lee, lead investigator on the study. "A biomarker like Ki-67 could be very important to chemoprevention studies in helping them progress much faster because there would be a biological standard to measure against. Plus, fewer participants would be needed for statistical evaluation and Ki-67 could help identify new molecular targets for intervention."

In the study, Dr. Lee and Dr. Walter N. Hittelman, measured the Ki-67 index in bronchial biopsy specimens from 120 current smokers and 207 former smokers. Sections of the specimens were stained to determine the metaplasia index, an indication of precancerous tissue changes, and stained with Ki-67 antibody to determine the proportion of proliferating cells.

The researchers report that biopsy sites with a high index of metaplasia had statistically higher proportions of proliferating cells, as indicated by the high index of Ki-67, than those without metaplasia in both current and former smokers. In individuals who had quit smoking, the proportion of proliferating cells dropped significantly, but remained detectable for more than 20 years, even in the absence of metaplasia.

According to the researchers, it is important to focus on early detection or chemoprevention methods because lung cancer remains the leading cause of cancer death for men and women in the United States. In 2000, there were more than 164,000 new cases of lung cancer and more than 156,000 deaths in the nation. Despite improvements in staging and treatment, the overall five-year survival rate stands at 14 percent, reports the American Cancer Society. Even if initial treatment is successful, the chance of developing second primary lung cancers is substantial, report the researchers.